The degree of behavioral control that an organism (rodent to human) can exert over an adverse event is arguably the most potent variable yet discovered that modulates the behavioral and neurochemical impact of that event. When the organism does have an element of control, the behavioral and neurochemical sequelae of the adverse event are blunted or eliminated. Research over the past grant period has indicated that control does so by activating ventral medial prefrontal cortical (vmPFC) top-down inhibitory control over stress- responsive limbic and brainstem structures. That is, when control is present, activation of stress-activated structures that are the proximate mediators of the behavioral changes, such as the dorsal raphe nucleus (DRN) & amygdala, is potently reduced. Importantly, research over the last part of the previous grant period has demonstrated that the experience of control not only blunts the impact of the stressor being controlled, but also blunts the impact of stressors experienced much later (at least one month), that is, control produces future resilience in the face of adversity. Moreover, preliminary evidence indicates that this occurs because the experience of control induces long-lasting plasticity in the vmPFC so that subsequent adverse events that would not normally induce vmPFC top-down inhibitory control, such as uncontrollable aversive events, now do so. Thus, the present proposal focuses on the vmPFC & its role in resilience and vulnerability. The research explores whether a) the vmPFC ic critical because it is part of a corticostriatal circuit; b) control confers long- term protection agaimnst stress because it induces plasticity in the corticostriatal circuit, and c) other manipualtions whih protect against stress effects also activate the corticostriatal circuit. PUBLIC HEALTH RELEVANCE: Exposure to major adverse events has profound effects on organismic functioning, & is an important etiological factor in the development of psychiatric disorders. However, there are large individual differences in the impact of such experiences, & so it is vital to understand factors that promote either vulnerability or resilience. Recent evidene suggests that experiencing behavioral control over adverse events produces resilience in the face of future adversity, and the proposed research explores the brain mechanisms that lead to resilience.